2-substituted 4-propargyloxymethyl-2-ethoxycarbonyl-gamma-butyrolactones

ABSTRACT

IN WHICH R is a saturated or unsaturated, straight or branched chain aliphatic hydrocarbon radical having one-10 carbon atoms or an aryl aliphatic radical, in which the aryl may be substituted by one or more halogen atoms, one or more alkoxy radicals or a trifluoromethyl radical. The compound is prepared by reacting, in the presence of sodium ethylate, (1) 4-propargyloxymethyl-2ethoxycarbonyl- gamma -butyrolactone with (2) XR, wherein R has the same meaning as above and X is halogen. The compounds possess respiratory stimulating, analgesic and hypotensive properties.   A compound of the formula

I [73] Assignee:

United States atent Fauran et al.

[54] Z-SUBSTITUTED 4- PROPARGYLOXYMETHYL-Z-ETHOXY- CARBONYL-y-BUTYROLACTONES [72] Inventors: Claude P. Fauran; Guy M. Raynaud, both of Paris; Bernard M. Pourrias, Meudon; Colette A. Douzon, Paris, all of France Delande S.A.

[22] Filed: Aug. 21, 1969 21 Appl. No.: 852,086

Wagner and Zook, Synthetic Organic Chemistry, Wiley & Sons, N.Y. 1953, pp. 346- 347 and 838 relied on.

[451 May 23, 1972 Primary Examiner-Alex Mazel Assistant Examiner-Anne Marie T. Tighe Att0mey-Woodhams, Blanchard and Flynn ABSTRACT A compound of the formula 0 HCECHC2OCH|-T -COOC2H5 in which R is a saturated or unsaturated. straight or branched chain aliphatic hydrocarbon radical having 1- 10 carbon atoms or an aryl aliphatic radical, in which the aryl may be substituted by one or more halogen atoms, one or more alkoxy radicals or a trifluoromethyl radical. The compound is prepared by reacting, in the presence of sodium ethylate, (l) 4-propargyloxymethyl-2-ethoxycarbonyl-y-butyrolactone with (Z) XR, wherein R has the same meaning as above and X is halogen. The compounds possess respiratory stimulating. analgesic and hypotensive properties.

5 Claims, N0 Drawings Z-SUBSTITUTED 4-PROPARGYLOXYMETHYL-2- ETHOXY-CARBONYL-y-BUTYROLACTONES The present invention concerns new substituted 4-propargyloxymethyl -2-ethoxycarbonyl --y-butyrolactone, their process of preparation, and their therapeutic application.

The compounds according to the present invention correspond to the general formula (I) in which R represents a saturated or unsaturated, straight or branched chain aliphatic radical having one to carbon atoms, or an arylaliphatic radical of which the aryl portion may be optionally substituted by one or more halogen atoms, one or more alkoxy radicals or a trifluoromethyl radical.

The process according to the present invention comprises reacting, in the presence of sodium ethylate, 4-propargyloxymethyl 2 ethoxycarbonyl e butyrolactone of the formula (II) and a halogen derivative of the formula:

XR in which X represents a halogen atom and R has the same significance as in formula l The following preparations are given an non-limitative examples to illustrate the present invention.

EXAMPLE 1 4-Propargyloxymethyl-2-Benzyl-2-ethoxycarbonylebutyrolactone.

6 g. of sodium is introduced, with agitation, into 400 cc. of absolute ethanol and after dissolution is complete, the temperature of the solution is raised to 50 C. 60 g. of 4-propargyloxymethyl-2-ethoxycarbonyl-e-butyrolactone is then added and maintained in contact for 1 hour. Whilst maintaining the temperature of the mixture at 50 C., 33g. of benzyl chloride are introduced and the mixture is kept under reflux for 3 hours. After cooling and adding 500 ml of water to dissolve the mineral salts formed, the ethanol is removed by distillation and the product formed is extracted with ethyl acetate. After decantation of the organic phase and removal of the solvent, a liquid product is obtained which is distilled.

Boiling point 190 C. under 0.1 mm. Hg.

Yield 83 percent Elementary analysis C H Calculated 68.34 6.37 Found 68.28 6.34

EXAMPLE 2.

of the organic phase, an oily residue is obtained which is purified by distillation.

Boiling point 206 C. under 0.05 mm. Hg.

Yield 60 percent Elementary analysis C H Cl Calculated 61.63 5.46 10.11

Found 61.74 5.45 10.26

EXAMPLE 3 Elementary analysis C H Calculated 64.66 5.73

Found 64.68 5.53

EXAMPLE 4 4-Propargyloxymethyl 2-p-methoxybenzyl 2-ethoxycarbonyl e-butyrolactone 4-Propargyloxymethyl 2-p-methoxybenzyl-2-ethoxycarbonyl e-butyrolactone is obtained according to the preceding examples by utilizing 4-pargyloxymethyl 2-ethoxycarbonyl-e-butyrolactone and p-methoxybenzyl chloride.

Boiling Point 2l0-220C under 0.05 mm. Hg.

Yield 40 percent Elementary Analysis C H Calculated 65.88 6.40 Found 65.66 6.43

The compounds of the present invention have been studies on animals in the laboratory and have been shown to possess, in particular, respiratory stimulating, analgesic and hypotensive properties.

1. RESPIRATORY STIMULATING PROPERTIES This action has been observed in the anaesthetised guineapig subject to respiratory depression provoked by the intraveinous injection of morphine hydrochloride. in these conditions, the compounds according to the present invention exert a favorable effect on the respiratory frequency and rhythm.

The results obtained with three of the compounds of general formula (I) areshown in Table I below:

2. ANALGESIC PROPERTIES The compounds of the present invention inhibit the painful stretchings provoked by the intraperitoneal injection of acetic acid in mice.

The results obtained with two of the compounds of general formula (I) as given in Table II below:

TABLE II Dose administcred, Percentage R. Mg./kg./PO protection C H Cl 100 40 E HYPOTENSIVE PROPERTIES The compounds according to general formula (ll are useful for the treatment of respiratory insufficiencies. pains and aches from various sources and arterial hypertension.

They are administered in the form of tablets or suppositories containing 50 to 400 mg of active ingredient, syrups or drops containing 0.5 to 10 percent of active ingredient or ampules containing 25 to 200 mg of active ingredient.

4-propargyloxymethyl-2-ethoxycarbonyl-e-butyrolactone can be prepared by the process described in U. S. Pat. application Ser. No. 851757, filed Aug. 20, 1969 by Claude P. Fauran, Guy M. Raynaud, Colette A. Douzon and Claude J. Gouret.

We claim:

1. A compound of the formula in which R is selected from the group consisting of hydrogen, halogen and lower alkoxy.

2. A compound according to claim I, in which R is hydrogen.

3. A compound according to claim 1, in which R is p-chloro. 4. A compound according to claim 1, in which R is p-fluoro. 5. A compound according to claim 1, in which R is pmethoxy. 

2. A compound according to claim 1, in which R is hydrogen.
 3. A compound according to claim 1, in which R is p-chloro.
 4. A compound according to claim 1, in which R is p-fluoro.
 5. A compound according to claim 1, in which R is p-methoxy. 